Paxlovid Works in High-Risk COVID, Says FDA Staff, but Drug Interactions a Concern

Nirmatrelvir-ritonavir (Paxlovid) wards off severe disease in high-risk COVID patients, but drug interactions at the individual level often disfavor its use, said FDA staff in briefing documents released ahead of an advisory committee meeting.

On Thursday, the Antimicrobial Drugs Advisory Committee will weigh in on the strength of evidence for use of the oral antiviral in outpatients at risk for severe outcomes, discuss concerns such as viral rebound and the numerous drug-drug interactions (DDIs), and finally recommend whether the overall risk-benefit assessment supports the standard approval of nirmatrelvir-ritonavir.

Currently, only remdesivir (Veklury) has full approval for treating high-risk patients with COVID-19, but the therapy is given over a 3-day intravenous course, limiting its use. Nirmatrelvir-ritonavir, given as a 5-day oral course soon after symptoms appear, has been widely used for high-risk COVID-19 since being granted emergency use authorization (EUA) in December 2021 based on findings from the phase III EPIC-HR (high risk) trial.

In that study, nirmatrelvir-ritonavir demonstrated an 86% relative reduction in the risk for COVID-related hospitalization or death from any cause through 28 days, with the primary composite outcome occurring at rates of 0.7% among patients assigned to the antiviral and 6.8% for those on placebo.

Subgroup analyses of EPIC-HR and a trial in standard-risk patients (EPIC-SR) showed the largest benefit in unvaccinated patients without a prior infection, FDA reviewers noted in the briefing documents, but also that a benefit remained in vaccinated individuals and those previously infected.

Across the two trials, the differences in COVID-related hospitalization or death for nirmatrelvir-ritonavir versus placebo were as follows:

• EPIC-SR vaccinated high-risk: <1% vs 2% (nominal P=0.2)
• EPIC-HR seropositive: <1% vs 2% (P=0.02)
• EPIC-HR seronegative: 2% vs 11% (P<0.0001)

“The EPIC-HR and EPIC-SR clinical trial results support the efficacy of Paxlovid for the treatment of mild-to-moderate COVID-19 in high-risk adults regardless of COVID-19 vaccination status or evidence of prior SARS-CoV-2 infection,” wrote FDA staff.

Moreover, they noted that the antiviral is currently one of just a few available COVID-19 treatments remaining in the outpatient setting, as monoclonal antibodies are not effective against the currently circulating Omicron subvariants. Other than remdesivir, only oral molnupiravir is still authorized for use in high-risk outpatients.

In a risk-benefit analysis, FDA reviewers said that nirmatrelvir-ritonavir’s reduction in COVID-related hospitalization and death among the “vaccinated or SARS-CoV-2 seropositive high-risk population remains a large benefit on a population level.”

Based on the 4,000 weekly deaths from COVID-19 and 35,000 weekly hospitalizations in January 2023 alone, they estimated that treatment with nirmatrelvir-ritonavir would have saved 1,500 lives per week and averted 13,000 hospitalizations, after factoring in that a quarter of eligible patients would be unable to take the antiviral due to DDIs and “with a conservative estimate of benefit” — a 50% reduction in relative risk.

Concern Over Drug-Drug Interactions

At the individual level, the benefit-risk calculus shifts as serious adverse events (AEs) due to DDIs are a “key safety concern” with nirmatrelvir-ritonavir, the FDA reviewers noted.

Patients with potential DDIs were excluded from the clinical trials of nirmatrelvir-ritonavir, but in these patients, “the risk could outweigh the benefit particularly if the DDIs are not adequately managed,” they wrote.

The bulk of the lengthy list of DDIs — which include common heart medications — stem from interactions with ritonavir, a potent cytochrome P450 (CYP) 3A inhibitor that increases the blood concentration of nirmatrelvir, making it more effective against SARS-CoV-2.

Ritonavir-containing products are commonly used to treat HIV or hepatitis C, where specialists typically oversee a patient’s care, but in the case of COVID-19 most prescriptions to date have been filled by primary care practitioners (74%) or emergency physicians (7%). Pharmacists can now prescribe the antiviral as well.

This broad range of prescribers “may not be familiar with ritonavir DDIs,” cautioned FDA staff.

According to data collected since the drug’s EUA, 301 AEs were deemed “possibly or probably related to DDIs.” Serious outcomes were observed in 271 cases, including 147 hospitalizations and six deaths (four related to concomitant tacrolimus use, one related to verapamil use, and one related to both nifedipine and atorvastatin).

“Despite mandatory AE reporting requirements, FDA is aware that not all AEs associated with Paxlovid were reported; therefore, the incidences of these events cannot be calculated based on these data,” FDA staff noted.

COVID Rebound

Previously a common concern with the antiviral (often dubbed Paxlovid rebound), the FDA was not able to find clear evidence associating COVID-19 viral rebound with nirmatrelvir-ritonavir, ultimately concluding based on analyses of EPIC-HR and EPIC-SR that “in a subset of SARS-CoV-2 infections, virologic and/or symptomatic rebound may occur as part of the natural progression and resolution of COVID-19 disease, irrespective of Paxlovid treatment.”